Islet Beta-Cell Specific Deletion of UBL5 Gene Associated with Mitochondrial Stress Leads to Diabetes in Mice and Beta-Cell Impairment/Death

Abstract

Hyperglycaemia has been shown to cause oxidative stress in pancreatic β-cells, leading to activation of stress responses such as the mitochondrial unfolded protein response (UPR^mt). Failure of these responses to adapt to or repair damage from stress results in dysfunction and death of β-cells. Ubiquitin-like protein 5 (UBL-5) is a protein known to have a crucial role in the UPR^mt in C. elegans and upregulated during the UPR^mt mammals.

The aim of this study was to determine whether UBL-5 has a role in maintaining β-cell mass and function through modulating the UPR^mt, by generating and characterising tamoxifen-inducible islet β-cell specific UBL-5 knockout mice. Homozygous β-cell UBL-5 knockout mice (UBL5-/-) showed glucose intolerance and lower plasma insulin levels during the OGTT while heterozygous mice (UBL5+/-) showed no difference. UBL5-/- had significantly reduced plasma insulin levels during IVGTT compared to control. Interestingly, UBL5+/- had significantly increased plasma insulin levels during IVGTT. Beta-cell mass was also significantly reduced in UBL5-/-, with most showing signs of frank diabetes (blood glucose >20 mM), polyuria and polydipsia, while UBL5+/- had increased β-cell mass. One week post UBL5 deletion, UBL5-/- mice had significantly increased blood glucose levels and islet cleaved caspase-3 levels compared to controls despite no difference in β-cell mass. In addition islets taken from UBL5-/- mice 1 week post UBL5 gene deletion showed significant decrease in insulin secretion, suggesting that β-cell dysfunction precedes the decrease in β-cell mass. Islets taken from UBL5+/- mice had increased insulin secretion compared to control. Real time PCR data showed a decrease in UPR^mt genes (Clpx, Clpp, CHOP, Lonp1, HSP10, HSP70, ATF5) with HSP60 showing increased expression in the UBL5-/- mice one week after gene deletion, while the UBL5+/- mice showed an overall increase in most UPR^mt related genes.